Keratin 18 provides resistance to Fas-mediated liver failure in mice.

ABSTRACT

BACKGROUND: Keratins are intermediate filament proteins of epithelial cells with pivotal functions for cell integrity. They comprise keratins 18 [K18] and 8 [K8] in hepatocytes. Keratins are of major importance for an intact cellular microarchitecture and have protective functions in human liver diseases. In mice, K8 has been demonstrated to protect against Fas-antibody-induced liver failure by direct interaction with apoptotic regulators, while the role of K18 remains unresolved. MATERIALS AND METHODS: We analysed effects of K18 deficiency on Fas-induced liver failure in mice. We determined survival and analysed induction of apoptosis after injection of the agonistic Fas antibody Jo2 into K18(-/-) and wild-type control mice by TUNEL assay and fluorometrically analysed caspase-3, -8 and -9 activities 1, 2 and 3 h after Jo2 injection. RESULTS: In K18(-/-) mice, survival of Fas-antibody treated mice was significantly shorter than that of wild-type controls (P = 0.02). However, shortened survival of K18(-/-) mice was caused by increased hepatic damage but was not correlated to enhanced induction of apoptotic pathways, as neither numbers of TUNEL positive apoptotic cells nor activities of caspases-3, -8 and -9 differed between K18(-/-) and K18(+/+) mice at any point of time. CONCLUSION: K18(-/-) mice are significantly more susceptible to Fas-antibody-induced liver failure. The cytoprotective effect of K18 is not explained by a differential activation of caspases-3, -8 and -9, suggesting that K18 does not directly interfere with apoptotic regulators. Importantly, however, K18 exerts significant protective functions by other mechanisms.